WO2017172979A1 - Composés quinazoline substitués et procédés d'utilisation - Google Patents

Composés quinazoline substitués et procédés d'utilisation Download PDF

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WO2017172979A1
WO2017172979A1 PCT/US2017/024839 US2017024839W WO2017172979A1 WO 2017172979 A1 WO2017172979 A1 WO 2017172979A1 US 2017024839 W US2017024839 W US 2017024839W WO 2017172979 A1 WO2017172979 A1 WO 2017172979A1
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alkyl
optionally substituted
carbocycle
membered heterocycle
halogen
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PCT/US2017/024839
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English (en)
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Liansheng Li
Jun Feng
Pingda Ren
Yi Liu
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Araxes Pharma Llc
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Priority to US16/089,000 priority Critical patent/US10822312B2/en
Publication of WO2017172979A1 publication Critical patent/WO2017172979A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/50—Perfumes

Definitions

  • Ras represents a group of closely related monomeric globular proteins of 189 amino acids (21 kDa molecular mass) which are associated with the plasma membrane and which bind either GDP or GTP. Ras acts as a molecular switch. When Ras contains bound GDP it is in the resting or off position and is "inactive". In response to exposure of the cell to certain growth promoting stimuli, Ras is induced to exchange its bound GDP for a GTP. With GTP bound, Ras is
  • Ras protein itself has a very low intrinsic ability to hydro lyze GTP back to GDP, thus turning itself into the off state. Switching Ras off requires extrinsic proteins termed GTPase- activating proteins (GAPs) that interact with Ras and greatly accelerate the conversion of GTP to GDP. Any mutation in Ras which affects its ability to interact with GAP or to convert GTP back to GDP will result in a prolonged activation of the protein and consequently a prolonged signal to the cell telling it to continue to grow and divide. Because these signals result in cell growth and division, overactive Ras signaling may ultimately lead to cancer.
  • GAPs GTPase- activating proteins
  • Ras proteins contain a G domain which is responsible for the enzymatic activity of Ras (e.g., guanine nucleotide binding and hydrolysis (GTPase reaction)). It also contains a C-terminal extension, known as the CAAX box, which may be post-translationally modified and is responsible for targeting the protein to the membrane.
  • the G domain is approximately 21-25 kDa in size and contains a phosphate binding loop (P-loop).
  • the P-loop represents the pocket where the nucleotides are bound in the protein; this is the rigid part of the domain with conserved amino acid residues which are essential for nucleotide binding and hydrolysis (Glycine 12, Threonine 26 and Lysine 16).
  • the G domain also contains the so called Switch I (residues 30-40) and Switch II (residues 60-76) regions, both of which are the dynamic parts of the protein which are often represented as the "spring-loaded” mechanism because of their ability to switch between the resting and loaded state.
  • Threonine-35 and glycine-60 form key hydrogen bonds with the ⁇ -phosphate of GTP, which maintain Switch I and Switch II regions, respectively, in their active conformation. After hydrolysis of GTP and release of phosphate, the regions relax into the inactive GDP conformation.
  • the most notable members of the Ras subfamily are HRAS, KRAS and NRAS, mainly for being implicated in many types of cancer.
  • G12C is a frequent mutation of K-Ras gene (glycine- 12 to cysteine). This mutation has been found in about 13% of cancer occurrences, including about 43% of lung cancer occurrences and almost 100% of MYH-associates polyposis (familial colon cancer syndrome). However targeting this gene with small molecules is a challenge.
  • the present disclosure provides a compound of Formula (I):
  • R 1 , R 2a , R 2b and R 2c are each independently selected from hydrogen and R ;
  • W and X are each independently selected from N, NR 5 and CR 6 ;
  • Z is selected from bond, N, and CR 6 ;
  • Y 1 is selected from -OR 55 ; and alkyl, alkenyl, alkynyl, C3-12 carbocycle and 3- to 12- membered heterocycle, each of which is substituted with -OR 55 and optionally futher substituted with one or more R 50 ;
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -
  • L is selected from bond and alkylene
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R 57 ;
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • R 5 is independently selected at each occurrence from R 51 ;
  • R 3a and R 3b are independently selected at each occurrence from H, -OH, -NH 2 , -C0 2 H, halo, cyano, Ci-6 alkyl, C 2- 6 alkynyl, hydroxylalkyl, aminoalkyl, alky lamino alkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl and aminocarbonyl; or R 3a and R 3b join to form oxo or a carbocyclic or heterocyclic ring; or R 3a is independently selected at each occurrence from H, -OH, -NH 2 , -C0 2 H, halo, cyano, Ci-6 alkyl, C 2- 6 alkynyl, hydroxylalkyl, aminoalkyl, alky lamino alkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl and aminocarbonyl, and R 3b joins with R 4b to form a carbocyclic or hetero
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • W, X and Z is CR 6 where R 6 is a bond to L .
  • R 2a and R 2b are each independently selected from hydrogen, halogen, -OH, -OR 52 , C 1-4 alkyl, and C 1-4 haloalkyl, wherein at least one of R 2a and R 2b is not hydrogen;
  • Y 2 is selected from -N(R 56 ) 2 ; and Ci-10 alkyl, C2-10 alkenyl and C2-10 alkynyl, each of which is substituted with -N(R 56 ) 2 and optionally futher substituted with one or more R 50 ;
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, - C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, -S(0)0-,
  • L is selected from bond and alkylene
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • R 56 is independently selected at each occurrence from:
  • Ci- 10 alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • G 1 and 2 are each independently N or CH;
  • R 3a and R 3b are independently selected at each occurrence from H, -OH, -NH 2 , -C0 2 H, halo, cyano, Ci-6 alkyl, C 2- 6 alkynyl, hydroxylalkyl, aminoalkyl, alky lamino alkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl and aminocarbonyl; or R 3a and R 3b join to form oxo or a carbocyclic or heterocyclic ring; or R 3a is independently selected at each occurrence from
  • R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
  • R 4a and R 4b are independently selected at each occurrence from H, -OH, -NH 2 , -C0 2 H, halo, cyano, Ci-6 alkyl, C 2- 6 alkynyl, hydroxylalkyl, aminoalkyl, alky lamino alkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl and aminocarbonyl; or R a and R join to form oxo or a carbocyclic or heterocyclic ring; or R 4a is independently selected at each occurrence from H, -OH, -NH 2 , -CO 2 H, halo, cyano, C 1-6 alkyl, C 2 -6 alkynyl, hydroxylalkyl, aminoalkyl, alky lamino alky 1, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl and aminocarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic
  • n 1 and m 2 are each independently 1, 2 or 3.
  • Y is selected
  • Y 2 is -N(R 56 ) 2 and the two R 56 groups are taken together with the nitrogen atom to which they are attached to form a heterocycle, wherein the heterocycle is optionally substituted with one or more R 5 J 0.
  • Y is - N(R 56 ) 2 and the two R 56 groups are taken together with the nitrogen atom to which they are attached to form a 3- to 6- membered heterocycle, wherein the heterocycle is substituted with -
  • R 1 may be selected from C 3 - 12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents selected from halogen, -N0 2 , 52 52
  • R 1 is selected from monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, and bicyclic heteroaryl. In some embodiments, R 1 is selected from phenyl, naphthyl, indazolyl, and quinolinyl. In some embodiments, R 1 is substituted with one or more substituents selected from halogen, -OH, -
  • R 1 is selected from:
  • R , R and R /c may each be independently selected from hydrogen, halogen, -OH, -OCH 3 , C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 2a and R 2b are each independently selected from halogen.
  • R 2a is fluorine.
  • R 2b is chlorine.
  • R 2c is hydrogen
  • C may be 5- to 8- membered heterocycle, optionally substituted with one or more R 57.
  • C is
  • C is selected from piperidinylene and piperazinylene, optionally substituted with one or more R 57. In some embodiments, C is selected from morpholinyl, piperidinylene and piperazinylene,
  • C is selected from , optionally substituted with one or more R . In some embodiments, C is selected from , and In some embodiments, R 57 is independently selected at each occurrence from C 1-6 alkyl, such as CH 3 .
  • T may be capable of forming a complex with a metal ion that is complexed with the Ras protein.
  • T is capable of forming an interaction with a mutation residue, such as G12D, in the Ras protein.
  • the mutation residue is selected from G12A, G12C, G12D, G12S and G12V.
  • T is selected from: -H, -NH 2 , -OH, -NH Ci -6
  • T is 0, 1, 2, or 3.
  • T is selected from R 57.
  • T is selected from hydrogen, -CH 3 , -C(0)H, -C(0)CH 3 , and -C(0)CH 2 CH 3 .
  • T is selected from hydrogen, -CH 3 , -C(0)H, -C(0)CH 3 , and -C(0)CH 2 CH 3 .
  • 52 52 is selected from hydrogen, C MO alkyl, Ci-io alkyl substituted with one or more R , -C(0)R , -
  • L 1 may be selected from bond and -N(R 51 )-, such as L1 is a bond.
  • L 2 is a bond.
  • R 1 may be selected from phenyl, naphthyl, indazolyl, and quinolinyl, optionally substituted with one or more substituents selected from halogen, -OH, and -CH 3 ;
  • R 2a and R 2b may each be independently selected from halogen;
  • R c may be hydrogen;
  • C may be 5 optionally substituted with one or more R 57 ;
  • T may be selected from hydrogen; and C 1-6 alkyl, optionally substituted with
  • L 1 and L 2 may each be a bond.
  • R 1 is .
  • R 57 is -CH 3 .
  • T is hydrogen.
  • R 1 may be selected from phenyl, naphthyl, indazolyl, and quinolinyl, optionally substituted with one or more substituents selected from halogen, -OH, and -CH 3 ;
  • R 2a and R 2b may each be independently selected from halogen;
  • R c may be hydrogen;
  • C may be ⁇ , optionally substituted with one or more R 57 ;
  • L 1 may be a bond.
  • the present disclosure provides a stereoisomer of a compound of Formula (III-
  • R 1 is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with one or more substituents independently selected from halogen, -OH, -OR 52 , - NH 2 , -NHMe, -NMe 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 3-12 carbocycle and 3- to 12-membered heterocycle;
  • R a and R are each independently selected from hydrogen, halogen, -OH, -OR , C 1-4 alkyl, and C 1-4 haloalkyl, wherein at least one of R 2a and R 2b is not hydrogen;
  • R 2c is selected from hydrogen, halogen, -OH, -OR 52 , C 1-4 alkyl, and C 1-4 haloalkyl; and Y 3 is selected from -OR 55 , -N(R 56 ) 2 ; and Ci-io alkyl, C 2-1 o alkenyl and C 2-1 o alkynyl, each of which is substituted with -OR 55 or -N(R 56 ) 2 and optionally futher substituted with one or more R 50 ;
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, - C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, -S(0)0-,
  • L is selected from bond and alkylene
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R 57 ;
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • R 51 is independently selected at each occurrence from:
  • R 55 is selected from:
  • Ci-10 alkyl C2-10 alkenyl, and C2-10 alkynyl, each of which is
  • R 56 groups are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • R 57 is independently selected at each occurrence from:
  • the compound may be provided as a substantially pure atropisomer.
  • the present disclosure provides a stereoisomer, such as an atropisomer, of a compound of Formula (I), (I- A), (I-B), (II), (II-A), (II-B) or (III-A).
  • the stereoisomer is provided in at least 90% enantiomeric excess. In some embodiments, the stereoisomer is provided in at least 90%
  • the present disclosure provides a compound selected from Table 1, Table 2 or Table 3.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound or salt of Formula (I), (I- A), (I-B), (II), (II- A), (II-B) or (III- A), and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for injection.
  • the present disclosure provides a method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition comprising a compound or salt of Formula (I), (I- A), (I-B), (II), (II- A), (II-B) or (III- A) to a subject in need thereof.
  • the cancer is mediated by a K-Ras, H-Ras, or N- Ras mutant protein.
  • the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.
  • the present disclosure provides a method for regulating activity of a K-Ras, H-Ras or N-Ras mutant protein, the method comprising contacting the Ras mutant protein with a compound or salt of Formula (I), (I-A), (I-B), (II), (II-A), (II-B) or (III-A).
  • the present disclosure provides a method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound or salt of Formula (I), (I-A), (I-B), (II), (II-A), (II-B) or (III-A).
  • inhibition of proliferation is measured as a decrease in cell viability of the cell population.
  • the present disclosure provides a method for treating a disorder mediated by a K-Ras, H-Ras or N-Ras mutant protein in a subject in need thereof, the method comprising: determining if the subject has a K-Ras, H-Ras or N-Ras mutation; and if the subject is determined to have the K-Ras, H-Ras or N-Ras mutation, then administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (I-B), (II), (II-A), (II-B) or (III-A).
  • a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (I-B), (II), (II-A), (II-B) or (III-A).
  • the disorder is a cancer, such as a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.
  • the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount of a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (I-B), (II), (II-A), (II-B) or (III-A) to a subject in need thereof.
  • the method further comprises administering a second anti-cancer agent.
  • Fig. 2 depicts a signal transduction pathway for Ras.
  • Fig. 3 shows some common oncogenes, their respective tumor type and cumulative mutation frequencies (all tumors).
  • C x-y or "C x -C y " when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
  • C x-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain.
  • Alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups.
  • An alkyl group may contain from one to twelve carbon atoms (e.g., C 1-12 alkyl), such as one to eight carbon atoms (C 1-8 alkyl) or one to six carbon atoms (C 1-6 alkyl).
  • Haloalkyl refers to an alkyl group that is substituted by one or more halogens.
  • haloalkyl groups include trifluoromethyl, difluoromethyl, trichloro methyl,
  • alkenyl refers to substituted or unsubstituted hydrocarbon groups, including straight- chain or branched-chain alkenyl groups containing at least one double bond.
  • An alkenyl group may contain from two to twelve carbon atoms (e.g., C 2-12 alkenyl).
  • Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-l-enyl, but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Alkynyl refers to substituted or unsubstituted hydrocarbon groups, including straight- chain or branched-chain alkynyl groups containing at least one triple bond.
  • An alkynyl group may contain from two to twelve carbon atoms (e.g., C 2-12 alkynyl).
  • Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • alkylene or "alkylene chain” refers to substituted or unsubstituted divalent saturated hydrocarbon groups, including straight-chain alkylene and branched-chain alkylene groups that contain from one to twelve carbon atoms. Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, “alkenylene” and “alkynylene” refer to alkylene groups, as defined above, which comprise one or more carbon-carbon double or triple bonds, respectively. The points of attachment of the alkylene, alkenylene or alkynylene chain to the rest of the molecule can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted by one or more substituents such as those substituents described herein.
  • Heteroalkyl refers to substituted or unsubstituted alkyl, alkenyl and alkynyl groups which respectively have one or more skeletal chain atoms selected from an atom other than carbon, e.g., O, N, P, Si, S or combinations thereof, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl has a chain length of 3 to 8 atoms.
  • Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain.
  • a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Hetero alkylene refers to substituted or unsubstituted alkylene, alkenylene and alkynylene groups which respectively have one or more skeletal chain atoms selected from an atom other than carbon, e.g., O, N, P, Si, S or
  • heteroalkylene, heteroalkenylene, or heteroalkynylene chain can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkyl, heteroalkenyl or heteroalkynyl chain.
  • a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted by one or more substituents such as those substituents described herein.
  • Carbocycle refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom.
  • Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • cyclopentane or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.
  • Heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms.
  • exemplary heteroatoms include N, O, Si, P, B, and S atoms.
  • Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings.
  • the heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the
  • heterocycle In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene.
  • heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl.
  • a heterocycle is optionally substituted by one or more substituents such as those substituents described herein.
  • Heteroaryl refers to a 3- to 12-membered aromatic ring that comprises at least one heteroatom wherein each heteroatom may be independently selected from N, O, and S.
  • the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the heteroatom(s) in the heteroaryl may be optionally oxidized.
  • One or more nitrogen atoms, if present, are optionally quaternized.
  • heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl,
  • benzothiadiazolyl benzo[ ] [l,4]dioxepinyl, benzo[b] [l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,
  • metal chelator or "metal chelator moiety” is any moiety capable of forming two or more separate coordinate bonds between the metal chelator group and a single central metal atom or metal ion.
  • Metal chelators typically have at least one pair of unbonded electrons which can bind to a metal atom or metal ion.
  • a metal chelator moiety comprises at least two heteroatoms selected from S, O, and N.
  • the metal chelator moiety is a bidentate or tridenate functional group.
  • a metal chelator moiety comprises a bidentate functional group selected from the group consisting of hydroxyamine, hydroxyamide, sulfonamide, urea, amide and oxime.
  • a metal chelator moiety comprises two or more monodentate functional groups selected from the group consisting of hydroxy, amino, ether, aldehyde, ketone, amide, thiol, thioether, heterocycle (e.g. imidazole) or oxime.
  • Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
  • the compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1H (protium),
  • Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.
  • Steps are isomers that differ only in the way the atoms are arranged in space.
  • Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • the term "effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
  • the specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.
  • compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • antagonists are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., K-Ras, H-Ras or N-Ras G12C). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.
  • Signal transduction is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response.
  • a modulator of a signal transduction pathway refers to a compound which modulates the activity of one or more cellular proteins mapped to the same specific signal transduction pathway.
  • a modulator may augment (agonist) or suppress (antagonist) the activity of a signaling molecule.
  • an "anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent” refers to any agent useful in the treatment of a neoplastic condition.
  • One class of anti-cancer agents comprises chemotherapeutic agents.
  • “Chemotherapy” means the administration of one or more
  • selective inhibition refers to a biologically active agent refers to the agent's ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B), or (II-C)).
  • a biologically active compound described herein e.g., compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B), or (II-C)
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • in vivo refers to an event that takes place in a subject's body.
  • in vitro refers to an event that takes places outside of a subject's body.
  • an in vitro assay encompasses any assay run outside of a subject.
  • In vitro assays encompass cell-based assays in which cells alive or dead are employed.
  • In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • the disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a
  • the present disclosure provides compounds that are capable of selectively binding to and/or modulating a Ras protein.
  • the Ras protien includes but is not limited to a mutant K-Ras, H-Ras or N-Ras protein.
  • the compounds modulate the Ras protein by binding to or interacting with one or more amino acids and/or one or more metal ions. Some subject compounds may also perturb the switch I conformation. The binding of these compounds may disrupt Ras (non-limiting examples include, K-Ras, H-Ras or N-Ras) downstream signaling.
  • the present disclosure provides a compound of Formula (I):
  • R 2a (I), or a salt thereof wherein: R l R 2a R 2b R 2c are each independently selected from hydrogen and R ; W and X are each independently selected from N, NR 5 and CR 6 ;
  • Z is selected from bond, N, and CR 6 ;
  • Y 1 is selected from -OR 55 ; and alkyl, alkenyl, alkynyl, C 3-12 carbocycle and 3- to 12- membered heterocycle, each of which is substituted with -OR 55 and optionally futher substituted with one or more R 50 ;
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, - C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, -S(0)0-,
  • L is selected from bond and alkylene
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R 57 ;
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • R 6 is independently selected at each occurrence from hydrogen, R 50 , and a bond to L 1 ;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • Ci-io alkyl C 2-1 o alkenyl, and C 2-1 o alkynyl, each of which is
  • n 1 and m 2 are each independently 1, 2 or 3.
  • R 3a , R 3b , R 4a and R 4b are independently selected at each occurrence from H, -OH, -NH 2 , -C0 2 H, halo, cyano, C 1-6 alkyl, hydroxylalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl and aminocarbonyl.
  • R 3a , R 3b , R 4a and R 4b are independently selected at each occurrence from hydrogen and C 1-6 alkyl, such as hydrogen and -CH 3 .
  • R 3b and R 4b are each H and R 3a and R 4a are independently selected at each occurrence from H, -OH, C 1-6 alkyl, hydroxylalkyl, cyano, and aminocarbonyl.
  • R 3a and R 4a are each H and R 3b and R 4b are independently selected at each occurrence from H, -OH, -NH 2 , -C0 2 H, halo, cyano, C 1-6 alkyl, hydroxylalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl and aminocarbonyl.
  • at least one of R 3a , R 3b , R 4a or R 4b is H.
  • a compound of Formula (I-B) is represented by a structure selected from:
  • R 1 is H, cyano, halo, Ci- 6 alkyl, C 1-6 alkylamino, C 3 -8 cycloalkyl, C 2 - 6 alkenyl, C 3 -8 cycloalkenyl, heterocyclyl, heteroaryl, aryloxy or aryl;
  • W and X are each independently N, NR 5 or CR 6 ;
  • Z is a bond, N or CR 6 ;
  • Y 1 is alkoxy, alkoxyalkyl, aminylalkoxy, arylalkoxy, heteroarylalkoxy, aryloxy or hetero aryloxy;
  • L 1 is a bond or NR 7 ;
  • L is a bond or alkylene
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R 3a or R 3b ;
  • R 5 J and R 7' are each independently H or C 1-6 alkyl
  • T is H or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • W, X or Z is CR 6 where R 6 is a bond to L 1 , and
  • Y 1 is not In some embodiments, when R 1 is 3- hydroxynaphthalenyl, T is -C(0)H, -C(0)CH 3 , or -C(0)CH 2 CH 3 , and C is unsubstituted by R 57 ,
  • R is 3 -hydroxynaphthalenyl
  • T is
  • Y 1 is selected from -OR 55 and -CH 2 OR 55 . In some embodiments, Y 1 is OR 55 . In some embodiments, Y 1 is
  • Y is an integer from 1 to 6, such as m is 2 or 3.
  • Y is an integer from 1 to 6, such as m is 2 or 3.
  • Y 1 is selected from -OR 55 ; and C MO alkyl, C 2-1 o alkenyl and C 2-1 o alkynyl, each of which is substituted with -OR 55 and optionally futher substituted with one or more R 50 .
  • R 55 is selected from:
  • the present disclosure provides a compound of Formula (I):
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, - C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, -S(0)0-,
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • R 55 is selected from:
  • R 57 is independently selected at each occurrence from:
  • W, X and Z is CR 6 where R 6 is a bond to L 1 ;
  • the present disclosure provides a compound of Formula (II)
  • Z is selected from bond, N, and CR 6 ;
  • Y 2 is selected from -N(R 56 ) 2 ; and alkyl, alkenyl, alkynyl, C3-12 carbocycle and 3- to 12- membered heterocycle, each of which is substituted with -N(R 56 ) 2 and optionally futher substituted with one or more R 50 ;
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, - C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, -S(0)0-,
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R 57 ;
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • R 51 is independently selected at each occurrence from:
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • R 56 groups are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • R 57 is independently selected at each occurrence from:
  • a compound of Formula (II) is represented by Formula (II- A):
  • R 3a and R 3b are independently selected at each occurrence from H, -OH, -NH 2 , -C0 2 H, halo, cyano, C 1-6 alkyl, C 2- 6 alkynyl, hydroxylalkyl, aminoalkyl, alky lamino alky 1, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl and aminocarbonyl; or R 3a and R 3b join to form oxo or a carbocyclic or heterocyclic ring; or R 3a is independently selected at each occurrence from
  • R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
  • R 3b and R 4b are each H and R 3a and R 4a are independently selected at each occurrence from H, -OH, C 1-6 alkyl, hydroxylalkyl, cyano, and aminocarbonyl.
  • R 3a and R 4a are each H and R 3b and R 4b are independently selected at each occurrence from H, -OH, -NH 2 , -C0 2 H, halo, cyano, C 1-6 alkyl, hydroxylalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl and aminocarbonyl.
  • at least one of R 3a , R 3b , R 4a or R 4b is H.
  • R 2a , R 2b and R 2c are each independently H, halo, hydroxyl, C 1-6 alkyl, C 1-6 halo alky 1, C 3 -8 cycloalkyl or aryl;
  • W and X are each independently N, NR 5 or CR 6 ;
  • Y is alkylamino, alkylamino alkyl, arylalkylamino, arylalkylamino alkyl,
  • L is a bond or alkylene
  • R 1 , R 2a , R 2b and R 2c are all independently selected from H and halo, then X and Z are both N and at least one of R 3a and R 3b is not H, and provided that at least one of
  • Y 2 is -CH 2 N(R 58 )CH 2 R 59 , wherein R 58 is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkyl substituted with halogen or -CN, C 3 - 6 carbocycle, and 3- to 6-membered heterocycle; and R 59 is selected from 3- to 8-membered heterocycle, optionally substituted with one or more halogens.
  • Y 2" is -CH 2 N(R 5 J 8 O )CH 2 R 5 J 9", wherein R 5 J 8 O is selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl; and R 59 is pyrimidinyl.
  • R 56 is independently selected at each occurrence from:
  • R 56 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 alkyl substituted
  • R 1 may contribute to the inhibitory activity of a compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II- C) (e.g., against K-Ras, H-Ras or N-Ras G12C).
  • R 1 is capable of forming a reversible interaction with a K-Ras, H-Ras or N-Ras G12C mutant protein.
  • R 1 is selected from monocyclic aryl, bicyclic aryl, monocyclic heteroaryl, and bicyclic heteroaryl. In some embodiments, R 1 is selected from phenyl, naphthyl, indazolyl, and quinolinyl. In some embodiments, R 1 is substituted with one or more substituents selected from bodiments, R 1 is selected from:
  • R 1 is In some embodiments, R 1 is selected from phenyl, naphthyl, indazolyl, and quinolinyl, substituted with one or more substituents selected from halogen, -OH,
  • quinolinyl substituted with one or more substituents selected from -F, -CI, -OH, -OCH 3 , -NH 2 , - CH 2 OH, Ci-4 alkyl, and Ci -4 haloalkyl.
  • R 1 is heterocyclyl, heteroaryl or aryl.
  • R 1 is aryl, such as phenyl or napthyl.
  • R 1 is unsubstituted aryl, such as unsubstituted phenyl or unsubstituted napthyl.
  • R 1 is substituted with one or more substituents.
  • the substituents are selected from halo, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy and C 3 -8 cycloalkyl. In some embodiments, the substituents are selected from fluoro, chloro, bromo, hydroxyl, methoxy and cyclopropyl. In some embodiments, the substituents are selected from -F, -CI, -OH, -OCH3, -NH 2 , -CH 2 OH, Ci -4 alkyl, and Ci -4 haloalkyl.
  • R 1 is substituted with one or more substituents selected from halo, cyano, cyanoCi. 6 alkyl, cyanoC 3 - 8 cycloalkyl, hydroxyl, Ci- 6 alkyl, Ci- 6 alkylcycloalky, C 2 - 6 alkynyl, Ci- 6 alkoxy, Q.
  • Ci- 6 alkylaminyl Ci- 6 alkylcarbonylaminyl, Ci- 6 hydroxylalkyl, Ci- 6 halo alkyl, Q. 6 alkoxyalkyl, aminosulfone, aminocarbonyl, aminocarbonylCi- 6 alkyl, aminocarbonylC 3 .
  • R 1 is substituted with one or more substituents selected from fluoro, chloro, bromo, cyano, hydroxyl, hydroxylmethyl, methoxy, methoxymethyl, ethyl, isopropyl, trifluoromethyl, aminocarbonyl and cyclopropyl.
  • R 1 is thiophenyl, pyridinyl, pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl, dihydroquinolinonyl,
  • R 1 is substituted with one or more substituents.
  • R 1 is substituted with one or more substituents selected from halo, C 1-6 alkyl, C 1-6 alkoxy, and C 2 -6 alkenylcarbonylaminyl.
  • R 1 is substituted with one or more substituents selected from halogen, hydroxy, and C 1-6 alkyl.
  • R 1 is substituted with one or more substituents selected from -F, -CI, -OH, and -CH 3 .
  • R 2a , R 2b and R 2c are each independently selected from hydrogen, halogen, -OH, C 1-4 alkyl, and C 1-4 haloalkyl.
  • R 2a and R 2b are each independently selected from halogen.
  • R 2a is fluorine.
  • R 2b is chlorine.
  • R 2c is hydrogen.
  • R 2a is fluorine
  • R 2b is chlorine
  • R c is hydrogen.
  • R a and R are each independently selected from halogen, and R 2c is hydrogen.
  • R 2a is hydrogen.
  • R 2a is halogen, such as chloro or fluoro.
  • R 2a is C 1-6 alkyl.
  • R 2a is C 3 -8 cycloalkyl, such as cyclopropyl.
  • C is selected from piperidinylene and piperazinylene, optionally substituted with one or more R 57.
  • C is piperazinylene, optionally substituted with one or more R 57 , such as piperazinylene substituted with 0, 1 or 2 R 57 substituents.
  • C is selected from , and , optionally
  • C is selected from 1 ⁇ 4 O N '1 , 5
  • R is independently selected at each occurrence from C 1-6 alkyl, such as -CH 3 .
  • C is selected from:
  • R 2a , R 2b and R 2c are each independently selected from hydrogen, halogen, C 1-4 alkyl, and Ci-4 haloalkyl;
  • R 2c is hydrogen
  • R 2a , R 2b and R 2c are each independently selected from hydrogen, halogen, -OH, -OCH 3 , Ci-4 alkyl, and C 1-4 haloalkyl;
  • R 1 is selected from phenyl, naphthyl, indazolyl, and quinolinyl, optionally substituted with one or more substituents selected from halogen, -OH, -OCH 3 , C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 2a , R 2b and R 2c are each independently selected from hydrogen, halogen, -OH, -OCH 3 , Ci-4 alkyl, and C 1-4 haloalkyl;
  • R 2a , R 2b and R 2c are each independently selected from hydrogen and halogen;
  • Y 1 is selected from -OR 55 and -CH 2 OR 55 ;
  • R 1 is selected from phenyl, naphthyl, indazolyl, and quinolinyl, optionally substituted with one or more substituents selected from halogen, -OH, -OCH 3 , C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 2a , R 2b and R 2c are each independently selected from hydrogen, halogen, C 1-4 alkyl, and Ci-4 haloalkyl;
  • Y is m 3 3 , wherein m is an integer from 1 to 6;
  • R is selected from
  • R a and R are each independently selected from halogen
  • T is selected from hydrogen, -CH 3 , -C(0)H, -C(0)CH 3 , and -C(0)CH 2 CH 3 ;
  • R 57 is independently selected at each occurrence from C 1-6 alkyl, such as -CH 3 .
  • R 2a , R 2b and R 2c are each independently selected from hydrogen and halogen;
  • Y 2 is selected from -N(R 56 ) 2 and -CH 2 N(R 56 ) 2 , wherein at least one R 56 is not hydrogen;
  • C is selected from piperazinylene, optionally substituted with one or more R 5 J 7';
  • R 1 is selected from phenyl, naphthyl, indazolyl, and quinolinyl, optionally substituted with one or more substituents selected from halogen, -OH, -OCH 3 , C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 2a , R 2b and R 2c are each independently selected from hydrogen, halogen, C 1-4 alkyl, and Ci-4 haloalkyl;
  • Y 2 is selected from -N(R 56 ) 2 and -CH 2 N(R 56 ) 2 , wherein at least one R 56 is not hydrogen;
  • C is selected from piperidinylene and piperazinylene, optionally substituted with one or more R 57 ; and
  • R 1 is selected from R 2a and R 2b are each independently selected from halogen;
  • R 2c is hydrogen
  • Y 2 is selected from -N(R 56 ) 2 and -CH 2 N(R 56 ) 2 , wherein at least one R 56 is not hydrogen;
  • C is selected from:
  • T is selected from hydrogen, -CH 3 , -C(0)H, -C(0)CH 3 , and -C(0)CH 2 CH 3 ;
  • R 57 is independently selected at each occurrence from C 1-6 alkyl, such as -CH 3 .
  • the present disclosure provides a compound of Formula (I- A):
  • R 1 is selected from Cs -12 carbocycle and 5- to 12-membered heterocycle
  • R 2a and R 2b are each independently selected from halogen, -OH, -OCH 3 , Ci
  • n 3 is an integer from 1 to 6;
  • L 1 and L 2 are each independently selected from bond and C 1-3 alkylene;
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R 57 ;
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • R 57 is independently selected at each occurrence from:
  • the present disclosure provides a compound of Formula (II- A):
  • R 1 is selected from Cs-i 2 carbocycle and 5- to 12-membered heterocycle
  • R 2a and R 2b are each independently selected from halogen, -OH, -OCH 3 , C 1-4 alkyl, and Ci-4 haloalkyl;
  • 2 c is selected from hydrogen, halogen, -OH, C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 59 is selected from 3- to 8-membered heterocycle, optionally substituted with one or more halogens;
  • L 1 and L 2 are each independently selected from bond and C1-3 alkylene
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R ;
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein; R is independently selected at each occurrence from:
  • the present disclosure provides a compound of Formula (II- A):
  • R 1 is selected from Cs-i 2 carbocycle and 5- to 12-membered heterocycle
  • R 2a and R 2b are each independently selected from halogen, -OH, -OCH 3 , Ci
  • R 58 is selected from hydrogen, Ci -4 alkyl, Ci -4 haloalkyl, Ci -4 alkyl substituted with halogen or -CN, C 3 -6 carbocycle, and 3- to 6-membered heterocycle; and R 59 is selected from 3- to 8-membered heterocycle, optionally substituted with one or more halogens;
  • L 1 and L 2 are each independently selected from bond and C1-3 alkylene
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R 57 ;
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • the present disclosure provides a stereoisomer of a compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C).
  • the stereoisomer is in enantiomeric excess.
  • the stereoisomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess.
  • the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer is in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess.
  • the present disclosure provides a stereoisomer of a compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C).
  • the stereoisomer is in diastereomeric excess.
  • the stereoisomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, diastereomeric excess.
  • the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, diastereomeric excess. In some embodiments, the stereoisomer is in greater than 95% diastereomeric excess, such as greater than 99% diastereomeric excess.
  • the present disclosure provides an atropisomer of a compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C).
  • the atropisomer is in enantiomeric excess.
  • the atropisomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess.
  • the atropisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, the atropisomer is in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess.
  • the compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II- B) or (II-C) is preferably used as a non-racemic mixture, wherein one atropisomer is present in excess of its corresponding enantiomer or epimer.
  • such mixture will contain a mixture of the two isomers in a ratio of at least about 9: 1, preferably at least 19: 1.
  • the atropisomer is provided in at least 96% enantiomeric excess, meaning the compound has less than 2% of the corresponding enantiomer.
  • the atropisomer is provided in at least 96% diastereomeric excess, meaning the compound has less than 2% of the
  • the compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II- B) or (II-C) is preferably used as a non-racemic mixture wherein the (+)-isomer is the major component of the mixture.
  • such mixture will contain no more than about 10% of the (-)-isomer, meaning the ratio of (+)- to (-)-isomers is at least about 9: 1, and preferably less than 5% of the (-)-isomer, meaning the ratio of (+)- to (-)-isomers is at least about 19: 1.
  • the compound used has less than 2% of the (-)-isomer, meaning it has an enantiomeric excess of at least about 96%. In some embodiments, the compound has an enantiomeric excess of at least 98%. In some embodiments, the compound has an enantiomeric excess of at least 99%.
  • the compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II- B) or (II-C) is preferably used as a non-racemic mixture wherein the (-)-isomer is the major component of the mixture.
  • such mixture will contain no more than about 10% of the (+)-isomer, meaning the ratio of (-)- to (+)-isomers is at least about 9: 1, and preferably less than 5% of the (+)-isomer, meaning the ratio of (-)- to (+)-isomers is at least about 19: 1.
  • the compound used has less than 2% of the (+)-isomer, meaning it has an enantiomeric excess of at least about 96%. In some embodiments, the compound has an enantiomeric excess of at least 98%. In some embodiments, the compound has an enantiomeric excess of at least 99%.
  • atropisomer s refers to conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetrical (i.e., optical activity arises without requiring an asymmetric carbon center or stereocenter). Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
  • Atropisomers are enantiomers (or epimers) without a single asymmetric atom.
  • Atropisomerism is defined to exist where the isomers have a half-life (ti /2 ) of at least 1000 seconds, which is a free energy barrier of 22.3 kcal mol “1 (93.3 kJ mol "1 ) at 300 K (Oki, M., "Recent Advances in Atropisomerism," Topics in Stereochemistry (1983) 14: 1).
  • the atropisomers are considered stable if the barrier to interconversion is high enough to permit the atropisomers to undergo little or no interconversion at room temperature for at least a week, preferably at least a year.
  • an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature during one week when the atropisomeric compound is in substantially pure form, which is generally a solid state. In some embodiments, an atropisomeric compound of the disclosure does not undergo more than about 5% interconversion to its opposite atropisomer at room temperature (approximately 25 °C) during one year. Preferably, the atropisomeric compounds of the disclosure are stable enough to undergo no more than about 5%
  • the present chemical entities, pharmaceutical compositions and methods are meant to include all such possible atropisomers, including racemic mixtures, diastereomeric mixtures, epimeric mixtures, optically pure forms of single atropisomers, and intermediate mixtures.
  • the energy barrier to thermal racemization of atropisomers may be determined by the steric hindrance to free rotation of one or more bonds forming a chiral axis. Certain biaryl compounds exhibit atropisomerism where rotation around an interannular bond lacking C2 symmetry is restricted.
  • the free energy barrier for isomerization (enantiomerization) is a measure of the stability of the interannular bond with respect to rotation. Optical and thermal excitation can promote racemization of such isomers, dependent on electronic and steric factors.
  • Ortho- substituted biaryl compounds may exhibit this type of conformational, rotational isomerism.
  • Such biaryls are enantiomeric, chiral atropisomers where the sp 2 -sp 2 carbon-carbon, interannular bond between the aryl rings has a sufficiently high energy barrier to prevent free rotation, and where substituents 1 ⁇ W2 and W 3 ⁇ W 4 render the molecule asymmetric.
  • the present disclosure provides at least 90% epimeric excess of an atropisomer selected from:
  • the present disclosure provides at least 90% enantiomeric excess of an atropisomer selected from:
  • the present disclosure provides a stereoisomer of a compound of Formula (I- A):
  • R is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is substituted with one or more substituents independently selected from halogen, -OH, -OR , - NH 2 , -NHMe, -NMe 2 , C 1-3 alkyl, C 1-3 haloalkyl, C 3-12 carbocycle and 3- to 12-membered heterocycle;
  • R 2a and R 2b are each independently selected from hydrogen, halogen, -OH, -OR 52 , C 1-4 alkyl, and C 1-4 haloalkyl, wherein at least one of R 2a and R 2b is not hydrogen;
  • R 2c is selected from hydrogen, halogen, -OH, -OR 52 , C 1-4 alkyl, and C 1-4 haloalkyl;
  • Y 1 is selected from -OR 55 ; and Ci-io alkyl, C 2-1 o alkenyl and C 2-1 o alkynyl, each of which is substituted with -OR 55 and optionally futher substituted with one or more R 50 ;
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, - C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, -S(0)0-,
  • L is selected from bond and alkylene
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R 57 ;
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein; R is independently selected at each occurrence from:
  • R 51 is independently selected at each occurrence from:
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • R 55 is selected from:
  • Ci- 10 alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • R 57 is independently selected at each occurrence from:
  • the stereoisomer of a compound of Formula (I- A) is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess.
  • the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer is in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess. In some embodiments, the stereoisomer of a compound of Formula (I- A) is an atropisomer.
  • the stereoisomer of a compound of Formula (I- A) is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, diastereomeric excess.
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, -
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • the stereoisomer of a compound of Formula (II- A) is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess.
  • the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer is in greater than 95% enantiomeric excess, such as greater than 99% enantiomeric excess. In some embodiments, the stereoisomer of a compound of Formula (II- A) is an atropisomer.
  • the stereoisomer of a compound of Formula (II- A) is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, diastereomeric excess.
  • R a and R are each independently selected from halogen. In some embodiments, R 1 , R 2a and R 2b are selected to produce an atropisomer.
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, - C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, -S(0)0-,
  • L is selected from bond and alkylene
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • R 55 is selected from:
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • R 56 is independently selected at each occurrence from: hydrogen;
  • R 57 is independently selected at each occurrence from:
  • the stereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%, diastereomeric excess. In some embodiments, the stereoisomer is in greater than 95% diastereomeric excess, such as greater than 99% diastereomeric excess. In some embodiments, the stereoisomer of a compound of Formula (III- A) comprises an atropisomer.
  • R a and R D are each independently selected from halogen. In some embodiments, R 1 , R 2a and R 2b are selected to produce an atropisomer.
  • Y 3 is selected from -OR 55 ;
  • L 1 is a bond
  • L 2 is a bond
  • R 57 is independently selected at each occurrence from:
  • the present disclosure provides a stereoisomer of a compound of Formula (III- A): (III- A), or a salt or prodrug thereof, wherein:
  • R 1 is selected from C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is
  • R 2a and R 2b are each independently selected from hydrogen, halogen, -OH, -OR 52 , C 1-4 alkyl, and C 1-4 haloalkyl, wherein at least one of R 2a and R 2b is not hydrogen;
  • Y 3 is selected from -OR 55 , -N(R 56 ) 2 , -SR 55 and S0 2 R 55 ; and C M0 alkyl, C 2 -io alkenyl and C 2- io alkynyl, each of which is substituted with -OR 55 , -N(R 56 ) 2 , -SR 55 or S0 2 R 55 and optionally futher substituted with one or more R 50 ;
  • L 1 is selected from bond, -0-, -S-, -N(R 51 )-, -N(R 51 )CH 2 -, -C(O)-, -C(0)0-, -OC(O)-, - OC(0)0-, -C(0)N(R 51 )-, -C(0)N(R 51 )C(0)-, -C(0)N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)-, - N(R 51 )C(0)N(R 51 )-, -N(R 51 )C(0)0-, -OC(0)N(R 51 )-, -C(NR 51 )-, -N(R 51 )C(NR 51 )-, - C(NR 51 )N(R 51 )-, -N(R 51 )C(NR 51 )N(R 51 )-, -S(0) 2- , -OS(O)-, -S(0)0-,
  • C is selected from 3- to 12-membered heterocycle, optionally substituted with one or more R 57 ;
  • T is hydrogen or a polar group capable of forming a complex with a Ras protein via an interaction other than one resulting in a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein;
  • R 50 is independently selected at each occurrence from:
  • Ci-io alkyl C 2- io alkenyl, and C 2- io alkynyl, each of which is
  • R 53 and R 54 are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • Ci-io alkyl C2-10 alkenyl, and C2-10 alkynyl, each of which is
  • R 56 groups are taken together with the nitrogen atom to which they are attached to form a heterocycle, optionally substituted with one or more R 50 ;
  • R 57 is independently selected at each occurrence from:
  • R 52 is further selected at each occurrence from halogen.
  • Y 1 is selected from -OR 55 , -SR 55 and S0 2 R 55 ; and alkyl, alkenyl, alkynyl, C3- 12 carbocycle and 3- to 12- membered heterocycle, each of which is substituted with -OR 55 , -SR 55 or S0 2 R 55 and optionally futher substituted with one or more R 50 .
  • Y 3 is selected from -OR 55 , -N(R 56 ) 2 , -SR 55 and S0 2 R 55 ; and C MO alkyl, C 2- i 0 alkenyl and C 2- 10 alkynyl, each of which is substituted with -OR 55 , -N(R 56 ) 2 , -SR 55 or S0 2 R 55 and optionally futher substituted with one or more R 50 .
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 °C to about 110 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • a compound of Formula A5 may be prepared according to
  • a compound of Formula B8 may be prepared according to
  • a compound of Formula C5 may be prepared according to
  • a compound of the present disclosure for example, a compound of a formula given in Table 1, Table 2 or Table 3 is synthesized according to one of the general routes outlined in Schemes 1-3, Examples 1-4, or by methods generally known in the art.
  • exemplary compounds may include, but are not limited to, a compound or salt therof selected from Table 1, Table 2, or Table 3.
  • compositions comprising any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for injection.
  • the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent).
  • additional therapeutic agent e.g., anticancer agent
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ- specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compound described herein is administered topically.
  • the compounds according to the disclosure are effective over a wide dosage range.
  • dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that are used in some embodiments.
  • An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • a compound of the disclosure is administered in a single dose.
  • such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly.
  • other routes are used as appropriate.
  • a single dose of a compound of the disclosure is used for treatment of an acute condition.
  • a compound of the disclosure is administered in multiple doses.
  • dosing is about once, twice, three times, four times, five times, six times, or more than six times per day.
  • dosing is about once a month, once every two weeks, once a week, or once every other day.
  • a compound of the disclosure and another agent are administered together about once per day to about 6 times per day.
  • the administration of a compound of the disclosure and an agent continues for less than about 7 days.
  • the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • Administration of the compounds of the disclosure may continue as long as necessary.
  • a compound of the disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days.
  • a compound of the disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day.
  • a compound of the disclosure is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • the compounds of the disclosure are administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics,
  • the compounds described herein are formulated into
  • compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
  • compositions comprising a compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C) and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).
  • the compounds described are administered as pharmaceutical compositions in which compounds of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C) are mixed with other active ingredients, as in combination therapy.
  • the pharmaceutical compositions include one or more compounds of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C).
  • a pharmaceutical composition refers to a mixture of a compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated.
  • the mammal is a human.
  • therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.
  • one or more compounds of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C) is formulated in an aqueous solutions.
  • the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • one or more compound described herein is/are formulated for transmucosal administration.
  • transmucosal formulations include penetrants that are appropriate to the barrier to be permeated.
  • appropriate formulations include aqueous or nonaqueous solutions.
  • such solutions include physiologically compatible buffers and/or excipients.
  • compositions described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients.
  • the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydro xypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium,
  • polyvinylpyrrolidone agar, or alginic acid or a salt thereof such as sodium alginate.
  • dosage forms such as dragee cores and tablets, are provided with one or more suitable coating.
  • concentrated sugar solutions are used for coating the dosage form.
  • the sugar solutions optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.
  • Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • push- fit capsules contain the active ingredients in admixture with one or more filler.
  • Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol.
  • stabilizers are optionally added.
  • therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration.
  • Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.
  • the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
  • formulations suitable for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations.
  • the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles.
  • Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • suspensions of the active compounds e.g., compounds of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C) are prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C) are administered topically.
  • the compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments.
  • Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive.
  • patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • the transdermal delivery of a compound described herein is accomplished by means of iontophoretic patches and the like.
  • transdermal patches provide controlled delivery of a compound described herein.
  • the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel.
  • absorption enhancers are used to increase absorption.
  • Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • the compounds of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II- B) or (II-C) are formulated for administration by inhalation.
  • Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists or powders.
  • compositions of any compound described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane,
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane,
  • the dosage unit of a pressurized aerosol is determined by providing a valve to deliver a metered amount.
  • capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C) are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like.
  • a low- melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.
  • compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising a compound described herein are
  • compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II- B) or (II-C), described herein as an active ingredient.
  • the active ingredient is in free-acid or free- base form, or in a pharmaceutically acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein.
  • the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, but are not limited to, gels, suspensions and creams.
  • compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • composition comprising at least one compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both.
  • a liquid composition includes a gel formulation.
  • the liquid composition is aqueous.
  • useful aqueous suspensions contain one or more polymers as suspending agents.
  • Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
  • Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound of Formula (I), (I- A), (I-B), (I-C), (II), (II- A), (II-B) or (II-C).
  • solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
  • Certain acceptable nonionic surfactants for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
  • useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
  • bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane
  • buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • compositions optionally include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • compositions include one or more surfactants to enhance physical stability or for other purposes.
  • Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and
  • polyoxyethylene alkylethers and alkylphenyl ethers e.g., octoxynol 10, octoxynol 40.
  • compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
  • aqueous suspension compositions are packaged in single-dose no n-reclo sable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.
  • the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents.
  • stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
  • polysorbate 20 (h) arginine, (i) heparin, (]) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
  • the concentration of one or more compounds provided in the pharmaceutical compositions of the present disclosure is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%,
  • the concentration of one or more compounds of the disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%,
  • the concentration of one or more compounds of the disclosure is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.

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Abstract

La présente invention concerne des inhibiteurs de la protéine Ras. L'invention concerne également des méthodes permettant de moduler l'activité de la protéine Ras et des méthodes de traitement de troubles médiés par la protéine Ras.
PCT/US2017/024839 2016-03-30 2017-03-29 Composés quinazoline substitués et procédés d'utilisation WO2017172979A1 (fr)

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